Brain communications最新文献

{"title":"Know your brain aging to know your resilience in neurodegenerative diseases.","authors":"Bryan Ng, Henrik Zetterberg","doi":"10.1093/braincomms/fcae467","DOIUrl":"10.1093/braincomms/fcae467","url":null,"abstract":"<p><p>This scientific commentary refers to 'Brain aging rejuvenation factors in adults with genetic and sporadic neurodegenerative disease', by Casaletto <i>et al</i>. (https://doi.org/10.1093/braincomms/fcae432).</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcae467"},"PeriodicalIF":4.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid-mediated resolution of inflammation and survival in amyotrophic lateral sclerosis.","authors":"Ozlem Yildiz, Guy P Hunt, Johannes Schroth, Gurleen Dhillon, Thomas P Spargo, Ammar Al-Chalabi, Sulev Koks, Martin R Turner, Pamela J Shaw, Sian M Henson, Alfredo Iacoangeli, Andrea Malaspina","doi":"10.1093/braincomms/fcae402","DOIUrl":"10.1093/braincomms/fcae402","url":null,"abstract":"<p><p>Neuroinflammation impacts on the progression of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Specialized pro-resolving mediators trigger the resolution of inflammation. We investigate the specialized pro-resolving mediator blood profile and their receptors' expression in peripheral blood mononuclear cells in relation to survival in ALS. People living with ALS (pwALS) were stratified based on bulbar versus limb onset and on key progression metrics using a latent class model, to separate faster progressing from slower progressing ALS. Specialized pro-resolving mediator blood concentrations were measured at baseline and in one additional visit in 20 pwALS and 10 non-neurological controls (Cohort 1). Flow cytometry was used to study the GPR32 and GPR18 resolvin receptors' expression in peripheral blood mononuclear cells from 40 pwALS and 20 non-neurological controls (Cohort 2) at baseline and in two additional visits in 17 pwALS. Survival analysis was performed using Cox proportional hazards models, including known clinical predictors and GPR32 and GPR18 mononuclear cell expression. Differential expression and linear discriminant analyses showed that plasma resolvins were able to distinguish phenotypic variants of ALS from non-neurological controls. RvE3 was elevated in blood from pwALS, whilst RvD1, RvE3, RvT4 and RvD1_{n-3 DPA} were upregulated in A-S and RvD2 in A-F. Compared to non-neurological controls, GPR32 was upregulated in monocytes expressing the active inflammation-suppressing CD11b⁺ integrin from fast-progressing pwALS, including those with bulbar onset disease (<i>P</i> < 0.0024), whilst GPR32 and GPR18 were downregulated in most B and T cell subtypes. Only GPR18 was upregulated in naïve double positive Tregs, memory cytotoxic Tregs, senescent late memory B cells and late senescent CD8⁺ T cells from pwALS compared to non-neurological controls (<i>P</i> < 0.0431). Higher GPR32 and GPR18 median expression in blood mononuclear cells was associated with longer survival, with GPR32 expression in classical monocytes (hazard ratio: 0.11, <i>P</i> = 0.003) and unswitched memory B cells (hazard ratio: 0.44, <i>P</i> = 0.008) showing the most significant association, along with known clinical predictors. Low levels of resolvins and downregulation of their membrane receptors in blood mononuclear cells are linked to a faster progression of ALS. Higher mononuclear cell expression of resolvin receptors is a predictor of longer survival. These findings suggest a lipid-mediated neuroprotective response that could be harnessed to develop novel therapeutic strategies and biomarkers for ALS.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcae402"},"PeriodicalIF":4.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Going 'meta': a systematic review of metacognition and functional neurological disorder.","authors":"Anna Sadnicka, Ann-Marie Strudwick, John P Grogan, Sanjay Manohar, Glenn Nielsen","doi":"10.1093/braincomms/fcaf014","DOIUrl":"10.1093/braincomms/fcaf014","url":null,"abstract":"<p><p>In functional neurological disorder (FND), there is a fundamental disconnect between an apparently intact nervous system and the individuals' ability to consistently perform motor actions, perceive sensory signals and/or access effective cognition. Metacognition, the capacity to self-evaluate cognitive performance, appears highly relevant to FND pathophysiology. Poor metacognition is a potential mechanism via which abnormal models of self and the state of the world could arise and persist unchecked. There is therefore a justified enthusiasm that studies of metacognition may give substance to FND's intangible nature. However, many assume an impairment in metacognition even though experimental studies are still in their infancy. This systematic review provides an analytical checkpoint of the evidence after the first five years of experimental work. We firstly summarize current methods for testing metacognition, prerequisite knowledge that allows readers to independently evaluate the evidence. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we then screened the 21 articles on this topic and review the experimental data of the eight studies that specifically tested metacognition in subjects with FND. Questionnaire metrics used to estimate global metacognition and general confidence in FND revealed a mixed picture of low or normal confidence. Of the five studies that used performance-controlled metrics, the gold-standard to estimate local metacognition in FND, four found metacognition to be equivalent to healthy controls and one paper supported impaired metacognition. We consequently try and broaden the debate and discuss alternative headline scenarios. We review how positive studies may offer insight and debate whether null studies could represent false negatives. However, since most studies find equivalent metacognition to controls, we also discuss whether metacognition could be intact and how this could inform mechanistic models of FND and have potential clinical utility. In summary, this review highlights signal of interest within the data, exposes current limitations and flags the many open questions.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf014"},"PeriodicalIF":4.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebrovascular reactivity: a stress test of brain vascular health in moyamoya disease.","authors":"Audrey P Fan, Meher R Juttukonda","doi":"10.1093/braincomms/fcae419","DOIUrl":"10.1093/braincomms/fcae419","url":null,"abstract":"<p><p>This scientific commentary refers to 'Cerebrovascular reactivity and response times describe recent ischemic symptomatology in patients with moyamoya', by Han <i>et al</i>.  (https://doi.org/10.1093/braincomms/fcae381).</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcae419"},"PeriodicalIF":4.1,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142973513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative susceptibility mapping is more sensitive and specific than phase imaging in detecting chronic active multiple sclerosis lesion rims: pathological validation.","authors":"Kelly M Gillen, Thanh D Nguyen, Alexey Dimov, Ilhami Kovanlikaya, Ha Manh Luu, Emily Demmon, Daniel M Markowitz, Francesca Bagnato, David Pitt, Susan A Gauthier, Yi Wang","doi":"10.1093/braincomms/fcaf011","DOIUrl":"10.1093/braincomms/fcaf011","url":null,"abstract":"<p><p>Quantitative susceptibility mapping and phase imaging are used to identify multiple sclerosis lesions with paramagnetic rims that slowly expand over time and are associated with earlier progression to disability, decreased brain volume and increased frequency of clinical relapse. However, the presence of iron-laden microglia/macrophages at the lesion rim and demyelination within the lesion both contribute to phase and quantitative susceptibility mapping images. Therefore, simultaneous pathological validation is needed to assess accuracies in identifying iron-positive lesions. MRI was performed on 15 multiple sclerosis brain slabs; 32 lesions of interest were processed for myelin, iron and microglial markers. Three experienced readers classified lesions as rim positive or negative on quantitative susceptibility mapping and phase; these classifications were compared with Perls' stain as the gold standard. All 10 of the quantitative susceptibility mapping-positive lesions had iron-positive rims on histology. Of the 16 phase-positive lesions, only 10 had iron-positive rims on histology. Using Perls' stain as the ground truth, the positive predictive value was 100% for quantitative susceptibility mapping and 63% for phase; the negative predictive value was 95% for quantitative susceptibility mapping and 94% for phase. Post-mortem imaging results demonstrate that quantitative susceptibility mapping is a more reliable indicator of an iron-positive rim compared with phase imaging.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf011"},"PeriodicalIF":4.1,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11800486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic characterization of Huntington's disease genetic modifiers informs drug target tractability.","authors":"Kevin Lucy Namuli, Alana N Slike, Mason A Hollebeke, Galen E B Wright","doi":"10.1093/braincomms/fcae418","DOIUrl":"10.1093/braincomms/fcae418","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Huntington's disease is caused by a CAG repeat in the &lt;i&gt;HTT&lt;/i&gt; gene. Repeat length correlates inversely with the age of onset but only explains part of the observed clinical variability. Genome-wide association studies highlight DNA repair genes in modifying disease onset, but further research is required to identify causal genes and evaluate their tractability as drug targets. To address these gaps and learn important preclinical information, we analysed genome-wide association study data from a large Huntington's disease age-of-onset study (&lt;i&gt;n&lt;/i&gt; = 9064), prioritizing robust candidate Huntington's disease modifier genes using bioinformatic approaches and analysing related information for these genes from large-scale human genetic repositories. We supplemented this information with other Huntington's disease-related screens, including exome studies of Huntington's disease onset and high-throughput assessments of mHTT toxicity. To confirm whether Huntington's disease modifiers are shared across repeat expansion disorders, we also analysed age-of-onset genome-wide association study data from X-linked dystonia-parkinsonism caused by a (CCCTCT)&lt;sub&gt;n&lt;/sub&gt; expansion. We also studied modifier-related associations with rare diseases to inform potential off-target therapeutic effects and conducted comprehensive phenome-wide studies to identify other traits linked to these genes. Finally, we evaluated the aggregated human genetic evidence and theoretical druggability of the prioritized Huntington's disease modifier genes, including characteristics recently associated with clinical trial stoppage due to safety concerns (i.e. human genetic constraint, number of interacting partners and RNA tissue expression specificity). In total, we annotated and assessed nine robust candidate Huntington's disease modifier genes. Notably, we detected a high correlation (&lt;i&gt;R&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt; = 0.78) in top age-of-onset genome-wide association study hits across repeat expansion disorders, emphasizing cross-disorder relevance. Clinical genetic repositories analysis showed DNA repair genes, such as &lt;i&gt;MLH1&lt;/i&gt;, &lt;i&gt;PMS2&lt;/i&gt; and &lt;i&gt;MSH3&lt;/i&gt;, are associated with cancer phenotypes, suggesting potential limitations as drug targets. &lt;i&gt;LIG1&lt;/i&gt; and &lt;i&gt;RRM2B&lt;/i&gt; were both associated with neurofibrillary tangles, which may provide a link to a potential role in mHTT aggregates, while &lt;i&gt;MSH3&lt;/i&gt; was associated with several cortical morphology-related traits relevant to Huntington's disease. Finally, human genetic evidence and theoretical druggability analyses prioritized and ranked modifier genes, with &lt;i&gt;PMS1&lt;/i&gt; exhibiting the most favourable profile. Notably, &lt;i&gt;HTT&lt;/i&gt; itself ranked poorly as a theoretical drug target, emphasizing the importance of exploring modifier-based alternative targets. In conclusion, our study highlights the importance of human genomic information to prioritize Huntington's disease modifier genes as drug targets, providing a basis for future t","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcae418"},"PeriodicalIF":4.1,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142973561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amyloid-β and tau deposition in traumatic brain injury: a study of Vietnam War veterans.","authors":"Hannah de Bruin, Colin Groot, Suzie Kamps, Everard G B Vijverberg, Anna Steward, Amir Dehsarvi, Yolande A L Pijnenburg, Rik Ossenkoppele, Nicolai Franzmeier","doi":"10.1093/braincomms/fcaf009","DOIUrl":"10.1093/braincomms/fcaf009","url":null,"abstract":"<p><p>Traumatic brain injury is widely viewed as a risk factor for dementia, but the biological mechanisms underlying this association are still unclear. In previous studies, traumatic brain injury has been associated with the hallmark pathologies of Alzheimer's disease, i.e. amyloid-β plaques and neurofibrillary tangles comprised of hyperphosphorylated tau. Depending on the type and location of trauma, traumatic brain injury can induce spatially heterogeneous brain lesions that may pre-dispose for the development of Alzheimer's disease pathology in aging. Therefore, we hypothesized that a history of traumatic brain injury may be related to spatially heterogeneous amyloid-β and tau pathology patterns that deviate from the stereotypical temporo-parietal patterns in Alzheimer's disease. To test this, we included 103 Vietnam War veterans of whom 65 had experienced traumatic brain injury (<i>n</i> = 40, 38.8% mild; <i>n</i> = 25, 24.3% moderate/severe). Most individuals had a history of 1 (<i>n</i> = 35, 53.8%) or 2 (<i>n</i> = 15, 23.1%) traumatic brain injury events. We included the group without a history of traumatic brain injury (<i>n</i> = 38, 36.9%) as controls. The majority was cognitively normal (<i>n</i> = 80, 77.7%), while a subset had mild cognitive impairment (<i>n</i> = 23, 22.3%). All participants underwent [¹⁸F]florbetapir/Amyvid amyloid-β PET and [¹⁸F]flortaucipir/Tauvid tau-PET 39.63 ± 18.39 years after their last traumatic brain injury event. We found no differences in global amyloid-β and tau-PET levels between groups, suggesting that a history of traumatic brain injury does not pre-dispose to accumulate amyloid-β or tau pathology in general. However, we found that traumatic brain injury was associated with altered spatial patterns of amyloid-β and tau, with relatively greater deposition in fronto-parietal brain regions. These regions are prone to damage in traumatic brain injury, while they are typically only affected in later stages of Alzheimer's disease. Moreover, in our traumatic brain injury groups, the association between amyloid-β and tau was reduced in Alzheimer-typical temporal regions but increased in frontal regions that are commonly associated with traumatic brain injury. Altogether, while acknowledging the relatively small sample size and generally low levels of Alzheimer's disease pathology in this sample, our findings suggest that traumatic brain injury induces spatial patterns of amyloid-β and tau that differ from patterns observed in typical Alzheimer's disease. Furthermore, traumatic brain injury may be associated with a de-coupling of amyloid-β and tau in regions vulnerable in Alzheimer's disease. These findings indicate that focal brain damage in early/mid-life may change neurodegenerative trajectories in late-life.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf009"},"PeriodicalIF":4.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11752645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low serum serotonin is associated with functional decline, mild behavioural impairment and brain atrophy in dementia-free subjects.","authors":"Ming Ann Sim, Yingqi Liao, Siew Pang Chan, Eugene S J Tan, Cheuk Ni Kan, Joyce R Chong, Yuek Ling Chai, Narayanaswamy Venketasubramanian, Boon Yeow Tan, Saima Hilal, Xin Xu, Christopher L H Chen, Mitchell K P Lai","doi":"10.1093/braincomms/fcaf005","DOIUrl":"10.1093/braincomms/fcaf005","url":null,"abstract":"<p><p>Brain serotonin dysregulation is associated with dementia and neuropsychiatric symptomology. However, the prognostic utility of circulating serotonin levels in detecting features of prodromal dementia including functional decline, cognitive impairment, mild behavioural impairment and brain atrophy remains unclear. In this prospective study of memory clinic subjects followed-up for ≤5 years, dementia-free subjects, classified as having no cognitive impairment or cognitive impairment, no dementia at baseline, underwent annual neuropsychological assessments including Montreal Cognitive Assessment, Global Cognition <i>Z-</i>scores and Clinical Dementia Rating Scale Global Scores (where a ≥ 0.5 increment from baseline denotes functional decline). Mild behavioural impairment was measured using baseline and annual Neuropsychiatric Inventory assessments, while brain atrophy was evaluated using cortical and medial temporal atrophy scores from baseline MRI scans. Baseline serum serotonin was then associated with the neuropsychological and neuroimaging measures cross-sectionally and longitudinally. Furthermore, associations of serum serotonin with cross-sectional brain atrophy scores were studied. Of the 191 elderly subjects included in the study, 63 (33.0%) had no cognitive impairment while 128 (67.0%) had cognitive impairment, no dementia. Fourteen subjects (9.0%) showed baseline mild behavioural impairment. Compared with the highest tertile, subjects within the lowest tertile of serotonin had greater Cortical Atrophy scores (adjusted odds ratio = 2.54, 95% confidence interval=1.22-5.30, <i>P</i> = 0.013). Serotonin levels were not significantly associated with cross-sectional neuropsychological or mild behavioural impairment scores (all <i>P</i> > 0.05). Of the 181 subjects with longitudinal cognitive follow-up (median duration 60.0 months), 56 (30.9%) developed functional decline, while incident mild behavioural impairment occurred in 26/119 (21.8%) subjects. Compared with the highest tertile, lower serotonin levels were associated with higher hazards of functional decline (lowest tertile: adjusted hazards ratio = 2.15, 95% confidence interval = 1.04-4.44, <i>P</i> = 0.039), and incident mild behavioural impairment (lowest tertile: adjusted hazards ratio = 3.82, 95% confidence interval = 1.13-12.87, <i>P</i> = 0.031, middle tertile: adjusted hazards ratio = 3.56, 95% confidence interval =1.05-12.15, <i>P</i> = 0.042). The association between the lowest serotonin tertile and functional decline was mediated via its effect on incident mild behavioural impairment (adjusted odds ratio = 3.96, 95% confidence interval = 1.15-13.61, <i>P</i> = 0.029). In conclusion, low circulating serotonin may be associated with cortical atrophy at baseline, as well as act as an early prognostic marker for functional decline and mild behavioural impairment in elderly, dementia-free subjects.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf005"},"PeriodicalIF":4.1,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning-based prediction of disease progression in primary progressive multiple sclerosis.","authors":"Michael Gurevich, Rina Zilkha-Falb, Jia Sherman, Maxime Usdin, Catarina Raposo, Licinio Craveiro, Polina Sonis, David Magalashvili, Shay Menascu, Mark Dolev, Anat Achiron","doi":"10.1093/braincomms/fcae427","DOIUrl":"https://doi.org/10.1093/braincomms/fcae427","url":null,"abstract":"<p><p>Primary progressive multiple sclerosis (PPMS) affects 10-15% of multiple sclerosis patients and presents significant variability in the rate of disability progression. Identifying key biological features and patients at higher risk for fast progression is crucial to develop and optimize treatment strategies. Peripheral blood cell transcriptome has the potential to provide valuable information to predict patients' outcomes. In this study, we utilized a machine learning framework applied to the baseline blood transcriptional profiles and brain MRI radiological enumerations to develop prognostic models. These models aim to identify PPMS patients likely to experience significant disease progression and who could benefit from early treatment intervention. RNA-sequence analysis was performed on total RNA extracted from peripheral blood mononuclear cells of PPMS patients in the placebo arm of the ORATORIO clinical trial (NCT01412333), using Illumina NovaSeq S2. Cross-validation algorithms from Partek Genome Suite (www.partek.com) were applied to predict disability progression and brain volume loss over 120 weeks. For disability progression prediction, we analysed blood RNA samples from 135 PPMS patients (61 females and 74 males) with a mean ± standard error age of 44.0 ± 0.7 years, disease duration of 5.9 ± 0.32 years and a median baseline Expanded Disability Status Scale (EDSS) score of 4.3 (range 3.5-6.5). Over the 120-week study, 39.3% (53/135) of patients reached the disability progression end-point, with an average EDSS score increase of 1.3 ± 0.16. For brain volume loss prediction, blood RNA samples from 94 PPMS patients (41 females and 53 males), mean ± standard error age of 43.7 ± 0.7 years and a median baseline EDSS of 4.0 (range 3.0-6.5) were used. Sixty-seven per cent (63/94) experienced significant brain volume loss. For the prediction of disability progression, we developed a two-level procedure. In the first level, a 10-gene predictor achieved a classification accuracy of 70.9 ± 4.5% in identifying patients reaching the disability end-point within 120 weeks. In the second level, a four-gene classifier distinguished between fast and slow disability progression with a 506-day cut-off, achieving 74.1 ± 5.2% accuracy. For brain volume loss prediction, a 12-gene classifier reached an accuracy of 70.2 ± 6.7%, which improved to 74.1 ± 5.2% when combined with baseline brain MRI measurements. In conclusion, our study demonstrates that blood transcriptome data, alone or combined with baseline brain MRI metrics, can effectively predict disability progression and brain volume loss in PPMS patients.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcae427"},"PeriodicalIF":4.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identify biological Alzheimer's disease using a novel nucleic acid-linked protein immunoassay.","authors":"Yi-Ting Wang, Nicholas J Ashton, Joseph Therriault, Andréa L Benedet, Arthur C Macedo, Ilaria Pola, Etienne Aumont, Guglielmo Di Molfetta, Jaime Fernandez-Arias, Kubra Tan, Nesrine Rahmouni, Stijn Johannes G Servaes, Richard Isaacson, Tevy Chan, Seyyed Ali Hosseini, Cécile Tissot, Sulantha Mathotaarachchi, Jenna Stevenson, Firoza Z Lussier, Tharick A Pascoal, Serge Gauthier, Kaj Blennow, Henrik Zetterberg, Pedro Rosa-Neto","doi":"10.1093/braincomms/fcaf004","DOIUrl":"10.1093/braincomms/fcaf004","url":null,"abstract":"<p><p>Blood-based biomarkers have been revolutionizing the detection, diagnosis and screening of Alzheimer's disease. Specifically, phosphorylated-tau variants (p-tau₁₈₁, p-tau₂₁₇ and p-tau₂₃₁) are promising biomarkers for identifying Alzheimer's disease pathology. Antibody-based assays such as single molecule arrays immunoassays are powerful tools to investigate pathological changes indicated by blood-based biomarkers and have been studied extensively in the Alzheimer's disease research field. A novel proteomic technology-NUcleic acid Linked Immuno-Sandwich Assay (NULISA)-was developed to improve the sensitivity of traditional proximity ligation assays and offer a comprehensive outlook for 120 protein biomarkers in neurodegenerative diseases. Due to the relative novelty of the NULISA technology in quantifying Alzheimer's disease biomarkers, validation through comparisons with more established methods is required. The main objective of the current study was to determine the capability of p-tau variants quantified using NULISA for identifying abnormal amyloid-β and tau pathology. We assessed 397 participants [mean (standard deviation) age, 64.8 (15.7) years; 244 females (61.5%) and 153 males (38.5%)] from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort where participants had plasma measurements of p-tau₁₈₁, p-tau₂₁₇ and p-tau₂₃₁ from NULISA and single molecule arrays immunoassays. Participants also underwent neuroimaging assessments, including structural MRI, amyloid-PET and tau-PET. Our findings suggest an excellent agreement between plasma p-tau variants quantified using NULISA and single molecule arrays immunoassays. Plasma p-tau₂₁₇ measured with NULISA shows excellent discriminative accuracy for abnormal amyloid-PET (area under the receiver operating characteristic curve = 0.918, 95% confidence interval = 0.883 to 0.953, <i>P</i> < 0.0001) and tau-PET (area under the receiver operating characteristic curve = 0.939; 95% confidence interval = 0.909 to 0.969, <i>P</i> < 0.0001). It also presents the capability for differentiating tau-PET staging. Validation of the NULISA-measured plasma biomarkers adds to the current analytical methods for Alzheimer's disease diagnosis, screening and staging and could potentially expedite the development of a blood-based biomarker panel.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf004"},"PeriodicalIF":4.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11753389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}